The present invention relates to novel 2-sulfamoylbenzoic acid derivatives which have an antagonistic effect on both the leukotriene D4 (hereinafter referred to simply as LTD4) receptor and the thromboxane A2 (hereinafter referred to simply as TXA2) receptor, intermediates for their synthesis and their salts and medicines containing them.
For treatment of allergic diseases including bronchial asthma, anti-allergic agents such as histamine receptor antagonists and mediator release suppressants for mast cells and steroid drugs have been used, and for bronchial asthma, bronchodilators such as xanthine derivatives and stimulators for the xcex2-sympathetic nerve receptor have been used as well.
In recent years, allergic diseases are recognized as allergic inflammations by their pathological profiles and have been found to be associated with various inflammatory cells and mediators. For example, bronchial asthma is characterized by increased sensitivity of the respiratory tract to various stimuli and defined as involving reversible stenosis of the respiratory tract, mucosal edema of the respiratory tract, mucous supersecretion and infiltration of inflammatory cells onto the walls of the respiratory tract.
Further, with respect to the related mediators, it is suggested that LTD4 not only has an intense bronchoconstrictor effect but also enhances the permeability of the respiratory tract vessels and mucus secretion, and that TXA2 not only has a potent bronchoconstrictor effect but also controls the sensitivity of the respiratory tract.
With the above-mentioned movements in research on treatment of allergic diseases, LTD4 receptor antagonists, TXA2 synthesis inhibitors and TXA2 receptor antagonists have been marketed and shown to be more effective than conventional anti-allergic agents.
However, because development of allergic diseases represented by bronchial asthma pathologically involves various mediators in parallel as mentioned above, antagonism against a receptor for a single mediator or inhibition of synthesis of a single mediator has its limit in terms of effect, and development of novel promising anti-allergic agents which show greater therapeutic effects by inhibiting both LTD4 and TXA2, major pathological mediators in allergy.
Compounds which have antagonistic effects on the receptors for both of the two mediators, LTD4 and TXA2, are disclosed in JP-A-3-258759, JP-A-4-154757, JP-A-4-154766, JP-A-5-262736, JP-A-5-279336, JP-A-6-41051 and WO96/11916. These compound are structurally different from the compounds of the present invention and are not expected to have satisfactory therapeutic effects as anti-allergic agents in view of the intensities of their antagonistic effects on the receptors for the major bronchoconstricting mediator LTD4 and the ratios of their antagonistic activities against the two mediators LTD4 and TXA2.
The present invention has been accomplished in view of the current situations in treatment of allergic diseases and research on their treatment with the aim of providing novel compounds which show potent antagonistic effects on the receptors for LTD4 and TXA2, which are the two major mediators in development of allergic diseases, and therefore are expected to have more excellent therapeutic effects and pharmaceuticals containing them as active ingredients.
In the above-mentioned movements in treatment of allergic diseases and research on their treatment, the present inventors have conducted extensive research with a view to attaining the above-mentioned object and, as a result, found out that the 2-sulfamoylbenzoic acid derivatives of the present invention have antagonistic effects on the receptors for the two mediators LTD4 and TXA2, which play important roles in development of allergic diseases, and have more excellent therapeutic effects than the above-mentioned receptor antagonists against a single mediator and inhibitors against synthesis of a single mediator. The present inventors have accomplished the present invention on the basis of this discovery.
Namely, the present invention provides 2-sulfamoylbenzoic acid derivatives represented by general formula (I): 
(wherein R1 and R2 which may be the same or different, are hydrogen atoms, C3-8 cycloalkyl groups, optionally substituted C1-6 alkyl groups, optionally substituted aryl groups or form, together with the ring 
a condensed ring represented by formula 
which may be substituted with an optionally substituted C1-6 alkyl group, an amino group, a cyano group, a nitro group, a hydroxyl group, a halogen atom or a C1-5 alkoxy group, X is an oxygen atom, a nitrogen atom, a sulfur atom or xe2x80x94CHxe2x95x90CHxe2x80x94, R3 is an optionally substituted phenylsulfonylamino group, an optionally substituted phenylsulfonyl group or an optionally substituted phenylsulfoxide group, R4 is a hydrogen atom or an ester residue, n is an integer of from 2 to 6, A is xe2x80x94Oxe2x80x94Bxe2x80x94, xe2x80x94Bxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Bxe2x80x94, xe2x80x94Bxe2x80x94Sxe2x80x94 or xe2x80x94Bxe2x80x94, and B is a C1-6 alkylene group or a C2-5 alkenylene group, provided that the cases wherein R1 is a C1-6 alkyl group, a C3-8 cycloalkyl group or a phenyl group, R2 is a hydrogen atom, A is a vinylene group, and X is a sulfur atom are excluded) or salts, hydrates or solvates thereof.
The present invention also provides, as useful intermediates for their synthesis, benzylamine derivatives represented by general formula (II): 
(wherein R1 and R2 which may be the same or different, are hydrogen atoms, C3-8 cycloalkyl groups, optionally substituted C1-6 alkyl groups, optionally substituted aryl groups or form, together with the ring 
a condensed ring represented by formula 
which may be substituted with an optionally substituted C1-6 alkyl group, an amino group, a cyano group, a nitro group, a hydroxyl group, a halogen atom or a C1-5 alkoxy group, X is an oxygen atom, a nitrogen atom, a sulfur atom or xe2x80x94CHxe2x95x90CHxe2x80x94, R3 is an optionally substituted phenylsulfonylamino group, an optionally substituted phenylsulfonyl group or an optionally substituted phenylsulfoxide group, n is an integer of from 2 to 6, A is xe2x80x94Oxe2x80x94Bxe2x80x94, xe2x80x94Bxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Bxe2x80x94, xe2x80x94Bxe2x80x94Sxe2x80x94 or xe2x80x94Bxe2x80x94, and B is a C1-6 alkylene group or a C2-5 alkenylene group, provided that the cases wherein R1 is a C1-6 alkyl group, a C3-8 cycloalkyl group or a phenyl group, R2 is a hydrogen atom, A is a vinylene group, and X is a sulfur atom are excluded) or salts thereof, benzaldehyde derivatives represented by general formula (IIIa): 
(wherein R1 and R2 which may be the same or different, are hydrogen atoms, C3-8 cycloalkyl groups, optionally substituted C1-6 alkyl groups, optionally substituted aryl groups or form, together with the ring 
a condensed ring represented by formula 
which may be substituted with an optionally substituted C1-6 alkyl group, an amino group, a cyano group, a nitro group, a hydroxyl group, a halogen atom or a C1-5 alkoxy group, Axe2x80x2 is xe2x80x94Bxe2x80x2xe2x80x94Oxe2x80x94 or xe2x80x94Bxe2x80x2xe2x80x94, and Bxe2x80x2 is a C1-6 alkylene group) or salts thereof, benzonitrile derivatives represented by general formula (IV): 
(wherein R1 and R2 which may be the same or different, are hydrogen atoms, C3-8 cycloalkyl groups, optionally substituted C1-6 alkyl groups, optionally substituted aryl groups or form, together with the ring 
a condensed ring represented by formula 
which may be substituted with an optionally substituted C1-6 alkyl group, an amino group, a cyano group, a nitro group, a hydroxyl group, a halogen atom or a C1-5 alkoxy group, and X is an oxygen atom, a nitrogen atom, a sulfur atom or xe2x80x94CHxe2x95x90CHxe2x80x94 or salts thereof and amine derivatives represented by general formula (V):
H2Nxe2x80x94(CH2)nxe2x80x94R3
(wherein n is an integer of from 2 to 6,and R3 is an optionally substituted phenylsulfonylamino group, an optionally substituted phenylsulfonyl group or an optionally substituted phenylsulfoxide group) or salts thereof. The present invention further provides a pharmaceutical, anti-allergic agent and leukotriene and thromboxane A2 antagonistic agent containing a 2-sulfamoylbenzoic acid derivative represented by general formula (I) or a salt, hydrate or solvate thereof as an active ingredient.
In general formulae (I), (II), (IIIa), (IV) and (V) mentioned above, a xe2x80x9cC3-8 cycloalkyl groupxe2x80x9d is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group, preferably a cyclopropyl group or a cyclobutyl group.
A xe2x80x9cC1-6 alkyl groupxe2x80x9d is a linear or branched alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group or a n-hexyl group, preferably an isopropyl group or a tert-butyl group.
An xe2x80x9coptionally substituted aryl groupxe2x80x9d is a carbocyclic aryl group such as a phenyl group or a naphthyl group, which may have, as a substituent, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a C1-6 alkyl group such as a methyl group or an ethyl group or a C1-5 alkoxy group such as a methoxy group or an ethoxy group, preferably a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group.
A xe2x80x9chalogen atomxe2x80x9d is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
A xe2x80x9cC1-5 alkoxy groupxe2x80x9d is a methoxy group, an ethoxy group, a n-propoxy group, a n-butoxy group, an isobutoxy group, a tert-butoxy group or a n-pentoxy group, preferably a methoxy group or an ethoxy group.
An xe2x80x9coptionally substituted phenylsulfonylamino groupxe2x80x9d, an xe2x80x9coptionally substituted phenylsulfonyl groupxe2x80x9d and an xe2x80x9coptionally substituted phenylsulfoxide groupxe2x80x9d may have, as a substituent, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a C1-6 alkyl group such as a methyl group or an ethyl group or a C1-5 alkoxy group such as a methoxy group or an ethoxy group, preferably a fluorine atom, a chlorine atom, a bromine atom, a methyl group or a methoxy group, at the ortho-position, meta-position, or para-position, preferably at the para-position.
An xe2x80x9cester residuexe2x80x9d is an ester residue such as a C1-6 alkyl group, a benzyl group, a phenethyl group or a 1-naphthyl group or an ester group metabolically hydrolysable in vivo such as a lower alkanoyloxy lower alkyl group like an acetyloxymethyl group, a lower alkenoyl lower alkyl group like a vinylcarbonylmethyl group, a cycloalkylcabonyloxy lower alkyl group like a cyclopropylcarbonyloxymethyl group, a lower alkenoyloxy lower alkyl group like a vinylcaronyloxymethyl group, a lower alkoxy lower alkyl group like a methoxymethyl group, a lower alkoxy lower alkoxy lower alkyl group like a methoxymethoxymethyl group, a lower alkoxycarbonyloxy lower alkyl group like a methoxycarbonyloxymethylmethyl group, a benzoyloxy lower alkyl group like a benzoyloxymethyl group, a 2-oxotetrahydrofuan-5-yl group or a 2-oxo-5-(lower alkyl)-1,3-dioxolen-4-ylmethyl group. Herein, xe2x80x9clowerxe2x80x9d means a linear or branched carbon chain having a carbon number of 1 to 6.
A xe2x80x9cC1-6 alkylene groupxe2x80x9d is a linear or branched alkylene group such as a methylene group, an ethylene group, a methylmethylene group, a trimethylene group, a propylene group, a dimethylmethylene group, a tetramethylene group, a 1-methyltrimethylene group, a 2-methyltrimethylene group, a 3-methyltrimethylene group, a 1-ethylethylene group, a 2-ethylethylene group, 2,2-dimethylethylene, 1,1-dimethylethylene, an ethylmethylmethylene group, a pentamethylene group, 1-methyltetramethylene, 2-methyltetramethylene, a 3-methyltetramethylene group, a 4-methyltetramethylene group, a 1,1-dimethyltrimethylene group, a 2,2-dimethyltrimethylene group, a 3,3-dimethyltrimethylene group, a 1,3-dimethyltrimethylene group, a 2,3-dimethyltrimethylene group, 1,2-dimethyltrimethylene, a 1,1,2-trimethylethylene group, a diethylmethylene group, a hexamethylene group, a 1-methylpentamethylene group, a 1,1-dimethyltetramethylene group or a 2,2-dimethyltetramethylene group, preferably a methylene group, an ethylene group, a propylene group, a methylmethylene group or a dimethylmethylene group.
A xe2x80x9cC2-5 alkenylene groupxe2x80x9d is a vinylene group, a propenylene group or a butenylene group, preferably a vinylene group.
The present invention covers the racemic bodies, diastereomers and any optical isomers of compounds of the present invention represented by general formulae (I), (II), (IIIa), (IV) and (V) which have one or more asymmetric carbon atom. Further, the present invention also covers any geometrical isomers of the compounds of the present invention inclusive of the (E)-forms, (Z)-forms and mixtures thereof.
As salts of the compounds of the present invention represented by general formulae (I), (II) , (IIIa), (IV) and (V), inorganic salts such hydrohalides such as hydrofluorides, hydrochlorides, hydrobromides and hydroiodides, nitrates, perchlorates, sulfates, phosphates and carbonates, lower alkylsulfonates such as methanesulfonates, trifluoromethanesulfonates and ethanesulfonates, arylsulfonates such as benzenesulfonates and p-toluenesulfonates, carboxylates such as acetates, fumarates, succinate, citrates, tartrates, oxalates and maleates, amino acid salts such as glycine salts, alanine salts, glutamates and aspartates and alkali metal salts such as sodium salts and potassium salts may be mentioned. As solvates, solvates with acetone, 2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuran and diethyl ether may be mentioned.
The compounds of the present invention represented by general formulae (I), (II), (IIIa), (IV) and (V) can be produced by the processes described below.
[Process A] Process for producing the compounds of the present invention represented by general formulae (I) and (II) 
(wherein R1, R2, X, R3, n and A are the same as defined above, and R4a is an ester residue.)
The first step is conventional reductive amination of an aldehyde represented by general formula (III) with an amine represented by general formula (V) and yields a benzylamine derivative represented by general formula (II).
This step is usually accomplished by in situ formation of an intermediary imine represented by general formula (IIxe2x80x2) from the aldehyde represented by general formula (III) and the amine represented by general formula (V) followed by reduction with an appropriate reducing agent. For formation of the intermediary imine, as the reaction solvent, methanol, ethanol, isopropanol, benzene or toluene is preferable, though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from 20xc2x0 C. to 140xc2x0 C., and the reaction time is preferably from 1 to 24 hours. For reduction of the intermediary imine, as the reducing agent, for example, sodium borohydride or lithium aluminum hydride is preferable, though any usual reducing agent that can reduce an imino group to an amino group can be used without any particular restriction. With respect to the amounts of the respective reactants, the compound of general formula (V) is used preferably in an amount of 1 to 5 equivalents based on the compound of general formula (III), and the reducing agent is used preferably in an amount of from 1 to 5 equivalents based on the compound of general formula (III). The reaction solvent is preferably methanol, ethanol or isopropanol though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from 0xc2x0 C. to 70xc2x0 C., and the reaction time is preferably from 30 minutes to 12 hours.
The second step is conventional sulfonamidation of the benzylamine derivative (II) obtained in the first step with a 2-chlorosulfonylbenzoic acid ester in the presence of a base and yields a 2-sulfamoylbenzoic acid derivative (Ia) which has an ester residue as R4 in general formula (I). The base may be either an aliphatic amine or an aromatic amine, preferably triethylamine or pyridine. With respect to the amounts of the respective reactants, the 2-chlorosulfonylbenzoic acid ester is used preferably in an amount of 1 to 3 equivalents based on the benzylamine derivative (II), and the base is used preferably in an amount of from 1 to 5 equivalents based on the benzylamine derivative (II). The reaction solvent is preferably chloroform, dichloromethane, 1,2-dichloroethane or 1,1,2,2-tetrachloroethane, though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from 0xc2x0 C. to 100xc2x0 C., and the reaction time is preferably from 30 minutes to 12 hours.
The third step is conventional hydrolysis of the compound of general formula (Ia) obtained in the second step and yields a compound of the present invention, wherein R4 is a hydrogen atom, represented by general formula (Ib). For this reaction, conventional hydrolysis in the presence of a base may be employed. The base is preferably a metal hydroxide or metal carbonate such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. With respect to the amounts of the respective reactants, the base is used preferably in an amount of 1 to 50 equivalents based on the ester compound (Ia). The reaction solvent is preferably water, methanol, ethanol, tetrahydrofuran or a mixture thereof though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from 0xc2x0 C. to 100xc2x0 C., and the reaction time is preferably from 30 minutes to 24 hours.
A compound (Ia) of the present invention is also obtainable by esterification of a compound (Ib) of the present invention which comprises conversion of the compound (Ib) of the present invention into an acid halide with a halogenating agent such as thionyl chloride, oxalyl chloride or thionyl bromide followed by treatment with an alcohol in the presence or absence of a base. For formation of the acid halide, as the reaction solvent, dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane or toluene is preferable, though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from 0xc2x0 C. to 100xc2x0 C., and the reaction time is preferably from 1 to 12 hours.
The base used for the esterification may be either an aliphatic amine or an aromatic amine, preferably triethylamine or pyridine. With respect to the amounts of the respective reactants, the alcohol is used preferably in an amount of from 1 to 10 equivalents based on the acid halide, and the base is used preferably in an amount of from 1 to 5 equivalents based on the acid halide. The reaction solvent may be dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, toluene or the alcohol used for the esterification, though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from 0xc2x0 C. to 80xc2x0 C., and the reaction time is preferably from 30 minutes to 12 hours.
A compound (Ia) of the present invention is also obtainable from a compound (Ib) of the present invention through reaction with an alcohol using a condensing agent such as dicyclohexylcarbodiimide, 1-ethyl-3-(3xe2x80x2-dimethylaminopropyl)carbodiimide or 1,1xe2x80x2-carbonyldiimidazol. The condensing agent is used preferably in an amount of from 1 to 2 equivalents based on the compound (Ib) of the present invention. The reaction solvent is preferably N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, dichloromethane, chloroform or 1,2-dichloroethane though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from 0xc2x0 C. to 70xc2x0 C., and the reaction time is preferably from 1 to 48 hours. In the cases of some types of reaction solvents, more than one equivalent of N-hydroxysuccinimide or N-hydroxybenzotriazole may be added beforehand so that the reaction proceeds smoothly.
[Process B] Process for producing the compounds (IIIb) of general formula (III) wherein X is a sulfur atom, and A is xe2x80x94CH2Oxe2x80x94
(wherein R1 and R2 are the same as defined above except that they do not form a condensed ring, and Hal is a bromine atom or a chlorine atom.)
Firstly, a compound represented by formula (a) reacts with a compound (b) in the presence of a base to give a compound (c). The base used for the reaction is preferably a metal carbonate such as potassium carbonate or sodium carbonate or a metal hydride such as sodium hydride or potassium hydride. As the reaction solvent, N,N-dimethylformamide, dimethyl sulfoxide or acetone may be mentioned, though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from 0xc2x0 C. to 100xc2x0 C., and the reaction time is preferably from 30 minutes to 8 hours. Then, the resulting compound (c) reacts with O,O-diethyl dithiophosphate (d) to give a compound (e). For the reaction, O,O-diethyl dithiophosphate is used preferably in an amount of from 1 to 5 equivalents based on the compound (c). The reaction solvent is preferably water or a solvent mixture of an organic solvent/water, though there is no particular restriction unless the reaction is considerably inhibited, and as the organic solvent, dimethoxyethane, tetrahydrofuran or acetone is preferable. The reaction temperature is preferably from 25xc2x0 C. to 100xc2x0 C., and the reaction time is preferably from 30 minutes to 8 hours. The resulting compound (e) reacts with a bromoketone represented by formula (f) to give a compound represented by general formula (IIIb). With respect to the amounts of the respective reactants, the bromoketone represented by formula (f) is used preferably in an amount of from 1 to 2 equivalents based on the compound (e). The reaction solvent is preferably a lower alcohol such as methanol, ethanol or isopropanol though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from 25xc2x0 C. to 100xc2x0 C., and the reaction time is preferably from 30 minutes to 24 hours.
[Process C] Process for producing the compounds (IIIC) of general formula (III) wherein A is xe2x80x94CH2Oxe2x80x94
(wherein R1, R2, X and Hal are the same as defined above.)
A compound represented by formula (g) and a compound (b) undergo alkylation in the presence of a base to give a compound represented by general formula (IIIC). As the base used for the reaction, a metal carbonate such as potassium carbonate or sodium carbonate or a metal hydroxide such as sodium hydride or potassium hydride is preferable, and the base is used preferably in an amount of from 1 to 10 equivalents based on the compound (b). As the reaction solvent, N,N-dimethylformamide, dimethyl sulfoxide or acetone may be mentioned, though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from 30xc2x0 C. to 100xc2x0 C., and the reaction time is preferably from 30 minutes to 8 hours.
[Process D] Process for producing the compounds (IIId) of general formula (III) wherein A is an ethylene group and the compounds of the present invention represented by general formula (IV) 
(wherein R1, R2, X and Hal are the same as defined above.)
A compound represented by formula (h) reacts with a compound (i) in the presence of a base to give a compound represented by formula (IV). As the base, an alkyl metal salt such as n-butyllithium, tert-butyllithium, lithium disiopropylamide or potassium tert-butoxide is preferably used. The base is used preferably in an amount of from 1 to 5 equivalents based on the compound of formula (h). As the reaction solvent, tetrahydrofuran, diethyl ether or toluene is preferable, though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from xe2x88x92100xc2x0 C. to 50xc2x0 C., and the reaction time is preferably from 30 minutes to 12 hours. The subsequent reduction of the nitrile group in the resulting compound represented by general formula (IV) with a reducing agent affords a compound represented by general formula (IIId). The reducing agent is preferably a metal hydride, particularly diisopropylaluminum hydride, though any reducing agent that can reduce a nitrile group into an aldehyde group may be used without any no particular restriction, and used in an amount of from 1 to 2 equivalents based on the compound of general formula (IV). As the reaction solvent, tetrahydrofuran, diethyl ether or toluene may be mentioned, though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from xe2x88x92100xc2x0 C. to 50xc2x0 C., and the reaction time is preferably from 30 minutes to 12 hours.
[Process E] Process for producing the compounds (IIId) of general formula (III) wherein A is an ethylene group 
(wherein R1, R2 and X are the same as defined above.)
Catalytic hydrogenation of a compound represented by general formula (IIIe) in the presence of a catalyst affords a compound represented by general formula (IIId). As the hydrogenation catalyst, 5% palladium carbon, 10% palladium carbon, 30% palladium carbon, platinum oxide or Wilkinson""s catalyst is preferable. The catalyst is used preferably in an amount of from {fraction (1/10)} to 1 time the weight of the compound (IIIe), and the hydrogen pressure is preferably from 1 to 5 atm. As the reaction solvent, methanol, ethanol, ethyl acetate or tetrahydrofuran is preferable, though there is no particular restriction unless the reaction is considerably inhibited. The reaction temperature is preferably from 25xc2x0 C. to 70xc2x0 C., and the reaction time is preferably from 1 to 72 hours.
[Process F] Process for producing the compounds (Va) of general formula (V) wherein R3 is an optionally substituted phenylsulfonyl group 
(wherein n and Hal are the same as defined above, P is a protecting group, and Z is a hydrogen atom, a halogen atom, a C1-6 alkyl group or a C1-5 alkoxy group.) An amino alcohol compound represented by formula (k) is converted into a compound of general formula (l) for protection of the amino group. The protection of the amino group can be accomplished by a conventional method using a protecting group such as a phthalimido group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group. The resulting compound of formula (l) is converted into a compound of formula (m) by replacement of the hydroxyl group with a halogen atom. The halogenation can be accomplished conventionally by bromination using phosphorus tribromide or carbon tetrabromide/triphenylphosphine or chlorination using thionyl chloride or phosphorus pentachloride. The resulting compound of formula (m) reacts with a thiophenol of formula (n) to give a compound of formula (o). The substitution can be accomplished by using a base such as potassium carbonate or sodium hydride. The resulting compound of formula (o) is oxidized to a compound represented by formula (p) and then finally converted into a compound of general formula (Va) through deprotection. For the oxidation, an oxidizing agent such as metachloroperbenzoic acid may be used. For the deprotection, conventional methods may be used according to the protecting group.
[Process G] Process for producing the compounds (Vb) of general formula (V) wherein R3 is an optionally substituted phenylsulfonylamino group 
(wherein n and Z are the same as defined above.)
A diamine compound represented by formula (q) reacts with a phenylsulfonyl chloride represented by formula (r) to give a compound of general formula (Vb). With respect to the amounts of the respective reactants, the diamine compound (q) is used preferably in an amount of from 1 to 20 equivalents based on the compound of formula (r). As the reaction solvent, chloroform, 1,2-dichloroethane, dichloromethane or 1,1,2,2-tetrachloroethane may be mentioned, though there is no particular restriction. The reaction temperature is preferably from 0xc2x0 C. to 50xc2x0 C., and the reaction time is preferably from 1 to 8 hours.
The compounds of the present invention and intermediates produced in the above-mentioned processes can be isolated in the forms of free compounds, salts, hydrates, solvates with various solvents such as ethanol or polymorphic crystals. Pharmaceutically acceptable salts of the compounds of the present invention are obtainable by conventional salt-forming reactions. Isolation can be accomplished through chemical techniques such as fractional extraction, crystallization and various types of fractional chromatography. Their optical isomers can be obtained as stereochemically pure isomers from appropriately selected starting materials or by racemic resolution of racemic compounds.
The 2-sulfamoylbenzoic acid derivatives of general formula (I) thus obtainable have an excellent anti-allergic effect by virtue of their antagonistic effects on both the LTD4 receptor and the TXA2 receptor and show excellent effects as preventive and therapeutic agents on allergic bronchial asthma, rhinitis and conjunctivitis, atopic dermatitis, gastroenteritis, colitis, vernal catarrh, nephritis and other allergic diseases. They are also useful as preventive and therapeutic agents for diseases associated with leukotrienes and TXA2 and widely applicable for prevention and treatment of ischemic heart and brain diseases, angina pectoris, inflammatory peptic ulcer and hepatopathy.
The 2-sulfamoylbenzoic acid derivatives of the present invention can be used by themselves or by using known drug formulations in various dosage forms, for example, for oral pharmaceuticals such as tablets, capsules, granules, fine granules, powders, liquids and syrups and for parenteral pharmaceuticals such as injections, nasal drops, eye drops, infusions, ointments, suppositories, inhalants, percutaneous pharmaceuticals and patches.
The dosages of the medicines of the present invention depend on the condition, age and body weight of the patient, the therapeutic effect and the mode and term of administration, but in the case of oral administration to an adult, they are usually administered in an amount of from 0.1 mg to 10 g per day.